PHGDH通过丝氨酸代谢途径调节HBV慢性感染中CD8+T细胞抗病毒免疫应答的机制研究

重构有效的抗HBV特异性CD8+T细胞免疫应答，是治疗慢性HBV感染的重要策略。丝氨酸生物合成途径在促进细胞增殖以及维持细胞稳态上具有重要的作用，但能否调节HBV慢性感染导致的CD8+T细胞的耗竭，目前尚无研究。在我们的前期研究工作中发现，在慢乙肝病人的CD8+T细胞中丝氨酸合成途径的限速酶--PHGDH表达降低。研究报道，耗竭的HBV特异性CD8+T细胞的免疫功能重建，已被证明依赖于线粒体的生物活性以及平衡ROS的产生。综上，我们推测，可以通过PHGDH介导的丝氨酸从头合成途径，增加NADPH和GSH的产生，平衡细胞内过量的ROS，激活线粒体的自噬能力，恢复细胞内稳态，改善或重建耗竭的HBV特异性CD8+T细胞的免疫功能。因此，我们利用PHGDH过表达和敲低（促进和阻断内源性丝氨酸合成）的体内、外模型，同时进行外源性丝氨酸干预，来验证上述假说。从而为临床慢乙肝的治疗提供新的思路。

Reconstructing an effective anti-HBV-specific CD8+T cell immune response is an important strategy for the treatment of chronic HBV infection. The serine biosynthetic pathway plays an important role in promoting cell proliferation and maintaining cell homeostasis, but whether it can regulate the depletion of CD8+T cells caused by chronic HBV infection has not yet been studied. In our previous research work, we found that the expression of the rate-limiting enzyme--PHGDH of the serine synthesis pathway was reduced in the CD8+T cells of patients with chronic hepatitis B. And it’s reported that the reconstruction of the immune function of exhausted HBV-specific CD8+T cells have been proven to depend on the biological activity and polarization ability of mitochondria, as well as the balance of ROS production. Therefore, we speculated that PHGDH-mediated de novo serine synthesis could increase the production of NADPH and GSH, neutralize excess ROS, activate mitochondrial autophagy, restore cell homeostasis, and improve or rebuild exhausted CD8+T Cellular immune function. Therefore, in vivo and in vitro models of PHGDH overexpression and knockdown (promoting and blocking the synthesis of endogenous serine) were used, as well as exogenous serine intervention, to verify the above hypothesis. The purpose is to provide new ideas for the clinical treatment of chronic hepatitis B.